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Mitochondria-Targeting Type-I Photodrug: Harnessing Caspase-3 Activity for Pyroptotic Oncotherapy
Zhigao Yi1,2, Xujuan Qin3,4, Li Zhang5
1Department of Chemistry, National University of Singapore, Singapore 117543, Singapore.
Abstract:
Precise control of cellular signaling events during programmed cell death is crucial yet challenging for cancer therapy. The modulation of signal transduction in cancer cells holds promise but is limited by the lack of efficient, biocompatible, and spatiotemporally controllable approaches. Here we report a photodynamic strategy that modulates both apoptotic and pyroptotic cell death by altering caspase-3 protein activity and the associated signaling crosstalk. This strategy employs a mitochondria-targeting, near-infrared activatable probe (termed M-TOP) that functions via a type-I photochemical mechanism. M-TOP is less dependent on oxygen and more effective in treating drug-resistant cancer cells, even under hypoxic conditions. Our study shows that higher doses of M-TOP induce pyroptotic cell death via the caspase-3/gasdermin-E pathway, whereas lower doses lead to apoptosis. This photodynamic method is effective across diverse gasdermin-E-expressing cancer cells. Moreover, the M-TOP mediated shift from apoptotic to pyroptotic modulation can evoke a controlled inflammatory response, leading to a robust yet balanced immune reaction. This effectively inhibits both distal tumor growth and postsurgical tumor recurrence. This work demonstrates the feasibility of modulating intracellular signaling through the rational design of photodynamic anticancer drugs.
Insights
This study introduces a novel photodynamic therapy using M-TOP, a mitochondria-targeting probe, to control cancer cell death pathways. It effectively treats drug-resistant and hypoxic cancers by modulating apoptosis and pyroptosis for enhanced immune response.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Photodynamic Therapy
Background:
- Controlling programmed cell death in cancer therapy is challenging.
- Existing methods lack biocompatibility and spatiotemporal control.
- Modulating cancer cell signaling offers therapeutic potential.
Purpose of the Study:
- To develop a photodynamic strategy for precise control of apoptotic and pyroptotic cell death.
- To investigate a mitochondria-targeting, near-infrared activatable probe (M-TOP) for cancer treatment.
- To explore M-TOP's efficacy in drug-resistant and hypoxic cancer cells.
Main Methods:
- Utilized a type-I photochemical mechanism with a mitochondria-targeting probe (M-TOP).
- Administered M-TOP at varying doses to modulate caspase-3 activity and signaling crosstalk.
- Tested efficacy in diverse gasdermin-E-expressing cancer cells, including drug-resistant and hypoxic models.
Main Results:
- M-TOP effectively modulated both apoptosis (lower doses) and pyroptosis (higher doses) via the caspase-3/gasdermin-E pathway.
- The strategy demonstrated efficacy in drug-resistant and hypoxic cancer cells.
- M-TOP induced a controlled inflammatory response, inhibiting tumor growth and recurrence.
Conclusions:
- Rational design of photodynamic drugs can modulate intracellular signaling for cancer therapy.
- M-TOP offers a versatile approach for controlling cell death pathways and enhancing anti-tumor immunity.
- This photodynamic strategy shows promise for treating challenging cancers and preventing recurrence.
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